Genetic Variant NCAM1:p.Asp260Asn (chr11-113207864-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_181351.5(NCAM1):c.778G>A(p.Asp260Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0124 in 1,611,398 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0096 ( 6 hom., cov: 32)

Exomes 𝑓: 0.013 ( 153 hom. )

Consequence

NCAM1
NM_181351.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.72

Publications

16 publications found

Variant links:

Genes affected

NCAM1 (HGNC:7656): (neural cell adhesion molecule 1) This gene encodes a cell adhesion protein which is a member of the immunoglobulin superfamily. The encoded protein is involved in cell-to-cell interactions as well as cell-matrix interactions during development and differentiation. The encoded protein plays a role in the development of the nervous system by regulating neurogenesis, neurite outgrowth, and cell migration. This protein is also involved in the expansion of T lymphocytes, B lymphocytes and natural killer (NK) cells which play an important role in immune surveillance. This protein plays a role in signal transduction by interacting with fibroblast growth factor receptors, N-cadherin and other components of the extracellular matrix and by triggering signalling cascades involving FYN-focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K). One prominent isoform of this gene, cell surface molecule CD56, plays a role in several myeloproliferative disorders such as acute myeloid leukemia and differential expression of this gene is associated with differential disease progression. For example, increased expression of CD56 is correlated with lower survival in acute myeloid leukemia patients whereas increased severity of COVID-19 is correlated with decreased abundance of CD56-expressing NK cells in peripheral blood. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Aug 2020]

NCAM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045161247).

BS2

High AC in GnomAd4 at 1468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAM1	NM_181351.5 link	c.778G>A	p.Asp260Asn	missense_variant	Exon 7 of 20	ENST00000316851.12	NP_851996.2	P13591-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAM1	ENST00000316851.12 link	c.778G>A	p.Asp260Asn	missense_variant	Exon 7 of 20	5	NM_181351.5	ENSP00000318472.8		P13591-2

Frequencies

GnomAD3 genomes

AF:

0.00965

AC:

1469

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00848

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.0107

AC:

2625

AN:

244738

AF XY:

0.0111

show subpopulations

Gnomad AFR exome

AF:

0.00238

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.0000563

Gnomad FIN exome

AF:

0.00956

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.0127

AC:

18515

AN:

1459126

Hom.:

153

Cov.:

AF XY:

0.0129

AC XY:

9358

AN XY:

725440

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

33452

American (AMR)

AF:

0.00495

AC:

220

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.0263

AC:

686

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00220

AC:

188

AN:

85356

European-Finnish (FIN)

AF:

0.00890

AC:

474

AN:

53282

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0145

AC:

16111

AN:

1110790

Other (OTH)

AF:

0.0112

AC:

673

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

947

1894

2842

3789

4736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00964

AC:

1468

AN:

152272

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

648

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41558

American (AMR)

AF:

0.00575

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0157

AC:

1066

AN:

68024

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0144

Hom.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00125

AC:

ESP6500EA

AF:

0.0139

AC:

116

ExAC

AF:

0.0113

AC:

1368

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.22

.;T;T;T;.;.;.;T;.;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0045

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.7

PrimateAI

Benign

0.30

REVEL

Benign

0.051

Sift4G

Benign

0.97

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.11, 0.21, 0.26, 0.32

.;.;.;.;.;.;.;B;B;B;B

Vest4

0.079

ClinPred

0.0051

GERP RS

4.7

Varity_R

0.19

gMVP

0.79

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over